The invention relates to a process for the purification and/or concentration of (radio)isotopes, a process for the purification of iodine isotopes, a process for obtaining a transportable form of isotopes and an apparatus therefore and a transportable form of isotopes.
Radiopharmaceuticals are used for diagnostic and therapeutic application in Nuclear Medicine. During the last decade, internal radiotherapy has become increasingly popular, particularly in the fields of oncology, endocrinology and rheumatology. Isotopes with a long half-life ( greater than 4 days) e.g. iodine-131 and strontium-89, have been in use for this kind of therapy. It is important that these isotopes emit xcex1- and/or xcex2-particles in order to achieve the desired absorbed radiation dose in target tissue (e.g. tumour tissue).
Diagnostic isotopes in general have a short half-life( less than 4 days) with a xcex3-decay (e.g. technetium-99 and iodine-123), and are used for localisation and visualisation of tumours, inflammation or metabolic diseases.
Radiopharmaceuticals are compounds that play an active role in the determination of biological processes by coupling to peptides or proteins. These compounds are labelled with an appropriate radio-isotope. The biologically active part is often responsible for seeking the target tissue. Diagnostic xcex3-emitting isotopes can be detected with a xcex3-camera to visualise the target tissue (e.g. tumour). The radiation dose for the patient will be kept as low as reasonable (ALARA=As Low As Reasonably Achievable principle). For therapeutical use, a high and selective uptake and long retention of the isotopes in the target is important in order to destroy the diseased tissue.
There is a large number of iodine isotopes which are used in nuclear medicine, especially for thyroid studies, where the (radio) iodine reacts with the tyrosine. Table 1 shows an overview of the most frequently used radio-iodinated compounds.
Radioiodine is an important radioisotope in nuclear medicine, for various applications (SPET, PET, and radioimmunotherapy). This wide-spread use in nuclear medicine implies meeting specifications, such as radionuclidic purity (e.g. low level of 121Te which is a by-product in the production of 123I) and radiochemical purity (e.g. absence of radioiodine containing impurities such as iodate or periodate compounds but also in the absence of 121Te, which is a by-product in the production of 123I).
Fulfilment of these requirements are a xe2x80x98conditio sine qua nonxe2x80x99 for an efficient production (high labelling yield) of radioiodinated pharmaceuticals. In earlier developed methods such as anion-exchange chromatography (Good et al., 1958, Harper et al., 1963) traces of (oxygenated) radioiodine containing impurities were not completely removed due to insufficient selectivity. The use of a distillation-process whether wet (Acerbi et al., 1975) or dry (Weinreich et al., 1996), is not only less practical, but in the case of no-carrier-added radioiodide, may also lead to hazardous and unwanted generation of impurities due to heating. Sometimes in these processes, presence of radioiodide impurities can be suppressed by addition of traces of reducing agents.
A concentration-purification process based on the adsorption/desorption features of radioiodide for platinum (Case et al., 1966, Kondo et al., 1977) has been described previously. In this method, radioiodide from an acidified solution was adsorbed, on a platinum surface (e.g. foil or felt), that was pre-treated with hydrogen-gas, and desorbed electrochemically (Toth, 1961), or by heating in a sulphite-containing alkaline-solution (Kondo et al., 1977). Adsorption and desorption were not quantitative (ca 80% and 60%, respectively), while the whole process is laborious and time consuming.
It is a goal of the present invention to provide a swift and reliable method for the purification of radioiodine. This method must be able to fulfil the high requirements for radiochemical purity as well as radionuclidic purity. The method should have a large capacity, contain little or no contamination with tellurium compounds, have a stable and reproducible yield and provide the radioisotope in the iodide form.
The method should also be capable of providing the radioiodide in a concentrated form, thus providing for a more efficient handling. Hence it is another goal of the invention to provide a method for the concentration of radioiodine.
It is also another goal of the present invention to provide for a method which is suitable as production-method, and is able to provide reductive properties for removing radiochemical impurities of the radioiodide, thereby obtaining a high recovery ( greater than 95%).
Accordingly, the invention comprises a process for the purification of radioisotopes wherein the isotopes are dissolved in a dilute acidic solution and adsorbed on a surface (optionally activated) of a d10-metal whereby the isotopes are selectively desorbed by elusion with an eluent in the presence of hydrogen.
It is possible that the terms iodide and iodine may be used in an interchangeable manner. This may be attributed to the mechanism of the adsorption-desorption process which is not fully elucidated. This does not detract from the concept and scope of the present invention.
Alterations on adsorption-material, as well as elution-conditions result in different embodiments of the invention and in an efficient process in which radiochemical pure radioiodide is obtained in a reproducible yield ( greater than 95%) with a high-recovery. A high yielding procedure comprising steps of the invention is one wherein a column is filled with the iodine absorbing metal such as platinum. The metal is optionally activated by purging with hydrogen gas. Subsequently an acidic solution containing the radioiodine is brought on the column and the radioiodine is absorbed on the metal. When platinum is used, the column has also reductive properties, thus reducing possible oxidation products of iodide such as iodate or periodate to iodine. After the iodide is absorbed, the column is rinsed to remove other impurities present in the load solution in such way that the iodide remains absorbed on the metal. Subsequently, the iodide is eluted in the form of iodine with a basic solution, optionally containing other components such as hydrogen. The purified iodine is collected and ready for further use.
By eluting the column with a suitable eluent the iodine is obtained in a concentrated form. One aspect of the invention therefore is a process for the concentration of radioisotopes wherein the isotopes are dissolved in a dilute acidic solution and adsorbed on the surface (optionally activated) of a d10-metal whereby the isotopes are selectively desorbed by elution with an eluent in the presence of hydrogen.
Another aspect of the invention relates to the combined concentration and purification of radioisotopes. Accordingly, the invention relates to a process for the purification and concentration of radioisotopes wherein the isotopes are dissolved in a dilute acidic solution and adsorbed on the surface (optionally activated) of a d10-metal whereby the isotopes are selectively desorbed by elution with an eluent in the presence of hydrogen.
In an preferred embodiment of the invention, the d10-metal is platinum.
In a preferred embodiment of the invention the metal is positioned in a column, whereby the column is filled with the iodine adsorbing metal. Any column, known in the art will suffice, such as a chromatography column, which can be a simple glass, metal or plastic column or tube of any size and diameter.
The metal can be in any suitable form, with or without a carrier material such as carbon, silica, alumina or other carrier materials which are itself known in the art. The form of the metal is not crucial, as long as the absorbing properties are suitable. In an embodiment of the invention the metal is in a form that allows for the formation of a column filled with the metal or metal-containing material. In a preferred embodiment, the metal is in the form of finely cut foil, sponge, powder or small particles, wherein the particle size of the metal ranges from 1 xcexcm to 2 mm, preferably from 2 xcexcm to 1.5 mm, more preferably from 5 xcexcm to 1 mm. A preferred embodiment is one wherein the metal particles have a size in the area of 10 to 20 xcexcm. Care should be taken that the metal particle size is selected such that the flow of the column is not blocked. When carrier materials are used, the size of the metal particles is not critical.
The surface of the metal which is used in the column may optionally be activated first by hydrogen. Thus, one embodiment of the invention is therefore one wherein the surface of the metal is activated by hydrogen, and another embodiment of the invention is one wherein the surface of the metal has not been activated.
The hydrogen optionally used to activate the surface of the metal is, in general, pure hydrogen. It is also possible to employ mixtures of inert gases with hydrogen, or solutions comprising hydrogen. It is another embodiment of the invention to generate hydrogen gas in situ, such as by the decomposition of formiate in H2 and CO2, which occurs at elevated temperatures, or by other compounds which, upon decomposition or otherwise, produce hydrogen or other compounds that activate the surface of the metal. It is therefore a preferred embodiment of the invention to activate the surface of the column by the decomposition of formiate.
The solution in which the isotopes are dissolved is an acidic solution. This can be any non-halogen containing acid such as nitric acid, sulphuric acid, phosphoric acid or other organic and inorganic acids, preferably sulphuric acid. An embodiment of the invention accordingly is one wherein the acidic solution is a sulphuric acid solution.
Elution of the column is accomplished by a basic solution, for instance an aqueous solution comprising hydroxide ions. The source of the hydroxide ions is not crucial, alkali hydroxides, earth alkali hydroxides and mixtures thereof can be used, preferably sodium or potassium hydroxide. In a preferred embodiment of the invention, the column is eluted with an aqueous solution of a hydroxide anion, wherein the alkaline solution has a concentration of OHxe2x88x92 from 10xe2x88x924 to 1 M, preferably 10xe2x88x923xe2x88x920.75 M, more preferably 5*10xe2x88x922xe2x88x920.5 M.
During optimisation it was found that a more optimal result was obtained by an alternating flux of the alkaline solution and hydrogen gas. By alternating elution of the column with a small volume of the alkaline solution and a small volume of hydrogen gas in a so-called xe2x80x98train elutionxe2x80x99 the efficiency was significantly improved. Therefore, in a preferred embodiment, the column is eluted by an alternating flux of the alkaline solution and hydrogen gas.
In an alternative embodiment it is also possible to elute the column with a compound which can generate hydrogen in situ. An example thereof is formiate. In an embodiment of the invention, the eluent comprises a solution of formiate. In a preferred embodiment of the invention the column is eluted by a solution comprising formiate, preferably at elevated temperatures.
In alternative embodiment of the invention the column is eluted under non-aqueous conditions. Preferably the solvent used in the anhydrous elution allows for a basic environment and at the same time dissolves iodide.
In an embodiment of the invention the isotope is selected from I- and At-isotopes, preferably from iodine isotopes, more preferably from 121I, 123I, 125I, 131I, most preferable 123I and 131I.
The iodine containing solution may also contain oxidation products of iodine. The oxygenated iodine products such as iodate and periodate are reduced in situ on the metal surface, thereby further improving the efficiency of the process of the purification of the iodine compounds.
The invention accordingly also relates to a process for the purification of solutions of iodine isotopes by the reduction of oxidised iodine containing compounds on an activated platinum, palladium or nickel metal, preferably platinum. The isolation can then be accomplished by selective eluting the reduced compounds. In an alternative embodiment the acidic solution therefore contains oxidised iodine compounds such as iodate or periodate. In an embodiment of the invention the metal has in situ reducing properties. The load solution which is generally directly obtained from the production step of radioactive iodine generally comprises the radioiodine and oxidised products of the radioiodine.
In another aspect the invention comprises a method for obtaining a concentrated and transportable form of radioisotopes whereby the iodine isotopes are absorbed on the column and eluted from the column prior to the use of the isotope. A preferred embodiment of the invention is therefore a kit comprising a column comprising platinum or palladium whereby an amount of iodine is absorbed on the metal and means for eluting said iodine. In this way it is possible to obtain the iodine free from oxidised products and ready for use.
The invention also comprises a process for the purification and concentration of radioiodine isotopes comprising the steps of:
a. optionally activating a platinum surface in a column with hydrogen gas,
b. loading the column with an acidic radioiodine solution
c. eluting the column.
The invention also comprises an apparatus for the purification of radioisotopes comprising a column, optional means for activating the metal, means for loading the column and means for eluting the column. In a preferred embodiment the invention comprises an apparatus for the purification of radioisotopes comprising a column, optional means for purging the column with hydrogen, means for loading the column, means for washing the column, means for eluting the column, means for collecting the eluted fraction and means for collecting waste.
The invention accordingly comprises a column comprising platinum and radioiodine, wherein the iodine is absorbed on the platinum and the invention also comprises a composition comprising platinum and iodine in a vessel suitable for storage and shipment.